The 2009 H1N1 pandemic influenza virus targets distal lung cells and causes diffuse alveolar damage in severe and fatal cases. Recent studies and our preliminary data indicate that there is variation in host susceptibility to this virus amon humans. Although animal studies provide valuable information on the effect of host genetic factors on the susceptibility to influenza, this information does not translate readily into the human situation and clinical medicine. We still do not know how the virus evades the host defense to cause lung injury in certain individuals, largely because it is difficult to study influnza patients directly. To address this issue, we have developed a primary culture system for human lung alveolar epithelial cells, the key targets for pandemic and avian flu. This will allow us to study the host response to influenza infection in the cells from deidentified donors. Our previous study indicates that interferon (IFN)-l is the predominant IFN produced by these cells during influenza infection. Additionally, a functional polymorphism in the IFN-l gene has been shown to be related to the outcome of viral clearance and responsiveness to hepatitis C virus in humans. However, whether this IFN-l polymorphism affects host response to respiratory viral infections is not known. In the proposed study, we will determine how the critical single nucleotide polymorphism (SNP) rs12979860 in the IFN-l3 gene affects host response to H1N1 pdm virus in human primary lung alveolar epithelial cells. In addition, we will investigate the role of IFN-l in influenza-induced epithelial injury in these cells. We hypothesize that SNP rs12979860 TT is associated with increased susceptibility to influenza infection and nonresponsiveness to IFN- l treatment. Our approach has three major novel features. First, studying the host response to the pandemic flu in our unique human primary culture system allows us to directly study the most relevant targets for the flu virus. Second, we will study the effect of the functional SNP in IFN-l on alveolar epithelial cell susceptibility to influenza and influenza-induced epithelial injury durng influenza infection. Third, we will study the function of IFN-l in limiting virus-induced epithelia injury. IFN-l is well known for its antiviral activity in epithelial cells, but whether it protectsthe epithelial barrier has not been studied. Our study will reveal novel information on the host genetic factors involved in regulating susceptibility and response to influenza infection, therefor providing novel approaches to improve influenza prevention strategies and develop better treatments for influenza- induced pathology. PUBLIC HEALTH RELEVANCE: Statement Influenza is a common public health problem responsible annually for more than 35,000 deaths, 200,000 hospitalizations, and more than $37.5 billion in economic loss (www.cdc.gov). According to the WHO, the recent 2009 H1N1 pandemic influenza virus led to over 18,000 verified deaths worldwide. This virus targets cells deep within the human lung that are responsible for gas exchange. However, the degree of clinical illness is highly variable, and therefore there must be some factors that alter host susceptibility. The proposed studies aim to determine whether variations in a key host antiviral factor, interferon-lambda, affect susceptibility of primary human lung epithelial cells to influenz infection and infection-induced lung injury. Results from these studies will reveal valuable information about risk factors within a population susceptible to influenza infection and provide novel approaches for the prevention and treatment of influenza-induced disease.